1. Field of the Invention
This invention relates to the clinical treatment of neurodegenerative diseases, including hereditary motor and sensory neuropathies (HMSN, also known as Charcot-Marie-Tooth disease), diabetic polyneuropathy, Alzheimer's pre-senile and senile dementia, Down's syndrome, Parkinson's disease, olivopontocerebellar atrophy, Huntington's disease, amyotrophic lateral sclerosis, age-onset neurological deterioration, alcoholic polyneuropathy, tinnitus, multiple sclerosis, and pathophysiologically symptomology.
2. Description of Prior Art
The logic and potential value, even synergistic value, of using two or more therapeutic agents in combination has been recognized previously (Ghose and coworkers, 1983; Goldstein and coworkers, 1990, pg. 102; Rinne, 1991). For example, in a study on two-drug combinations of memory enhancing agents Flood and coworkers (1988) noted that:
The potential for clinically desirable drug interactions has been emphasized for drugs in general (1) and for memory enhancing drugs in particular (2,3). For example, individual cholinergic drugs which improve memory retention test scores (4,5,6) do so in two-drug combinations at substantially lower doses than would be predicted if the two drugs acted additively (7,8,9) . . . PA1 In prior studies of the effect of two-drug combinations on memory processing (8,9), we determined the effect of varying the dose of two drugs while holding the ratio constant. The ratio was based on the optimal memory enhancing doses of each drug administered singly. These studies showed that drugs administered in certain combinations require 67 to 96% less drug to improve retention, than when the same drugs were administered alone. This type of drug interaction was said to yield supra-additivity. PA1 . . The development of clinical features in AD [Alzheimer's disease] is linked to the amount of deposition of amyloid in the limbic areas and cerebral cortex. Moreover, amyloid formation may arise as a consequence of membrane damage . . . due to lipid peroxidation . . . About 6% of PHF [paired helical filaments] is composed of the amino-acid, hydroxyproline. This amino-acid is not a constituent of cytoplasmic protein in normal brain and the abundance of hydroxyproline in cytoplasmic PHF involves non-enzymatic hydroxylation of proline residues probably by hydroxyl free radicals. This free radical hypothesis of PHF formation suggests that AD is an acceleration of the normal aging process in affected brain regions. PA1 Both capillary GC and LC results appear to implicate aldehydes (both normal and unsaturated) and related compounds, furan derivatives, as characteristic products of lipid peroxidation. Elevated aldehyde levels were also noticed in our earlier investigations of urinary metabolites of both long-term diabetic rats and genetically diabetic mice. Since an increased lipid peroxidation process has been associated with the diabetic condition, it is not surprising that known peroxidation metabolites should be more abundant in diabetic than normal urine samples . . . Increased lipid peroxidation clearly results in a greater production of metabolites that are either proven or suspected neurotoxins. PA1 aminoalkyl derivatives of the formula PA1 amino(hydroxyalkyl)-derivatives of the formula PA1 aminoalkyl-ether-derivatives of the formula PA1 amino(hydroxyaklyl)-ether-der-ivatives of the formula PA1 H.sub.2 N--C.sub.6 H.sub.4 --(CH.sub.2).sub.n -[carbohydrate], PA1 H.sub.2 N--CH.sub.2 --C.sub.6 H.sub.4 --(CH.sub.2).sub.n -[carbohydrate], PA1 H.sub.2 N--C.sub.6 H.sub.4 --(CH.sub.2).sub.n --O-[carbohydrate] where n=0-30, and PA1 H.sub.2 N--C.sub.6 H.sub.4 --(CH.sub.2).sub.m --CHOH--(CH.sub.2).sub.n --O-[carbohydrate] where m=0-15 n=0-15 PA1 H.sub.2 N--C(.dbd.NH)-[carbohydrate]; PA1 H.sub.2 N--C(.dbd.NH)--(CH.sub.2).sub.n -[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--C(.dbd.NH)--O--(CH.sub.2).sub.n -[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--C(.dbd.NH)--NH-[carbohydrate]; PA1 H.sub.2 N--C(.dbd.NH)--NH--(CH.sub.2).sub.n -[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--C(.dbd.NH)--NH--(CH.sub.2).sub.n --O-[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--C(.dbd.NH)--N.dbd.CH--(CH.sub.2).sub.n -[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--C(.dbd.NH)--N.dbd.CH--(CH.sub.2).sub.n --O-[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--NCH(.dbd.NH)--NH-[carbohydrate]; PA1 H.sub.2 N--NCH(.dbd.NH)--NH--(CH.sub.2).sub.n -[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--NCH(.dbd.NH)--NH--(CH.sub.2).sub.n --O-[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--NCH(.dbd.NH)--N.dbd.CH--(CH.sub.2).sub.n -[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--NCH(.dbd.NH)--N.dbd.CH--(CH.sub.2).sub.n --O-[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--C(.dbd.NH)--NH--NH-[carbohydrate]; PA1 H.sub.2 N--C(.dbd.NH)--NH--NH--(CH.sub.2).sub.n -[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--C(.dbd.NH)--NH--NH--(CH.sub.2).sub.n --O-[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--C(.dbd.NH)--NH--N.dbd.CH--(CH.sub.2).sub.n -[carbohydrate], where n=1-10, including hydrocarbon isomers and hydroxylated derivatives thereof; PA1 H.sub.2 N--C(.dbd.NH)--NH--N.dbd.CH--(CH.sub.2).sub.n --O-[carbohydrate], where n=1-10, including hydrocarbon isomers, ether linkage isomers and hydroxylated derivatives thereof; PA1 pantothenic acid, 250 mg; PA1 beta-carotene, 25,000 I.U.; PA1 selenium (Osco, Oak Brook, Ill.), 50 .mu.g; PA1 vitamin B.sub.1, 100 mg; PA1 and one Osco brand "balanced B complex 50" tablet, each tablet consisting of: PA1 . . it may take as long as 18 months before regenerating axons reach the distal denervated muscles where the site of the lesion lay in proximal nerve roots or plexuses. In neuronopathies, where cell death has occurred, any degree of recovery can only occur by peripheral sprouting from axons of surviving neurons. This also appears to be a relatively slow process. Hence, therapeutic trials must extend for long enough to ensure that the slow biological reparative processes can be detected.
The present disclosure describes the inventive concept of using the therapeutic technology of U.S. patent application Ser. No. 08/026,617, filed Feb. 23, 1993, now abandoned in combination witch pharmaceutical agents previously recognized as having, or possibly having some medicinal value for treatment of the disease entities noted above. No pharmacological treatment of comprehensive effectiveness is currently available for any of the neurological disorders discussed herein. However, a variety of pharmaceutical agents have been described which may offer at least some degree of symptomatic relief from the clinical effects of these diseases.
The 16th edition of the Merck Manual (Berkow, 1992, pp. 1497-1499) has defined symptomatic clinical treatment of Parkinson's disease to consist of: (a) oral co-administration of levodopa, the metabolic precursor of dopamine, and carbidopa, a peripheral decarboxylase inhibitor [in compositions such as Sinemet CR]; (b) co-agent use of amantadine HCl [Symmetrel; 1-amino-adamantane, a rye ergot alkaloid and neuronal transmission enhancer]; (c) co-agent use of ergot alkaloids such as bromocriptine mesylate [Parlodel, which has a dopamine agonist activity for D.sub.2 receptors and antagonist activity at D.sub.1 receptors] and pergolide mesylate [Permax, a dopamine-receptor agonist active at both D.sub.1 and D.sub.2 receptor subtypes (Robin, 1991)]; (d) selegiline HCl [Eldepryl, a selective inhibitor of monoamine oxidase B which prolongs the action of dopamine (Rinne, 1991)]; (e) co-agent use of anticholinergic medications such as benztropine mesylate [Cogentin], trihexylphenidyl [Artane], procyclidine [Kemadrin], biperiden and ethopropazine [Paridol]; (f) co-agent use of antihistamines such as diphenhydramine [Benadryl] and orphenadrine; (g) co-agent use of tricyclic antidepressants such as amitriptyline, imipramine, nortriptyline and doxepin; and (h) co-agent use of propranolol.
Other well established or experimental therapeutic approaches for clinical treatment of Parkinson's disease, which may or may not be used in conjunction with L-dopa, have been publicly disclosed. These include possible use of (a) selegiline in combination with tocopherol (Greenamyre and O'Brien, 1991); (b) D-cycloserine with or without a cholinesterase inhibitor co-agent (Francis and coworkers, 1991); (c) other dopamine receptor agonists such as (+)-4-propyl-9-hydroxynaphthoxazine (Martin and coworkers, 1984), apomorphine and ciladopa (Koller and coworkers, 1986; Goldstein and coworkers, 1990); (d) neurotransmission enhancer drugs such as lisuride, a rye ergot alkaloid (Rinne, 1989; Rinne, 1991); (e) known antioxidants such as ascorbic acid, alpha-tocopherol, beta-carotene (Mathews-Roth, 1987), N-acetylcysteine (Smilkstein and coworkers, 1988), penicillamine or cysteamine (Harris, 1982), as increased levels of lipid peroxidation are apparent in parkinsonian tissue (Ceballos and coworkers, 1990; Fahn, 1989); (f) other peripheral decarboxylase inhibitors such as benserazide (Madopar HBS) (Pinder and coworkers, 1978; Pletscher, 1990); and (g) N-methyl-D-asparate (NMDA) glutamate receptor antagonists such as dizocilpine (Clineschmidt and coworkers, 1982; Woodruff and coworkers, 1987) and milacemide (Youdim, 1988; Ferris, 1990) or use of the possible antagonist 1-amino-3,5-dimethyl adamantane (Memantine) (Fischer and coworkers, 1977; Schmidt and coworkers, 1990; Greenamyre and O'Brien, 1991); (h) tacrine (Cognex, an experimental agent of Warner-Lambert Co.) and a hydroxy derivative thereof, (.+-.)-9-amino-1,2,3,4-tetrahydroacridin-1-ol (Shutske and coworkers, 1988); and (i) tiapride (Price and coworkers, 1978).
Since activation of NMDA glutamate receptors has also been implicated in the etiologies of Huntington's disease, amyotrophic lateral sclerosis, olivopontocerebellar atrophy and Alzheimer's disease, use of NMDA glutamate receptor antagonists such as those listed above may be of clinical benefit for patients having these diseases (Woodruff and coworkers, 1987; Greenamyre and O'Brien, 1991; Giuffra and coworkers, 1992), as well as for patients suffering from certain neurodegenerative effects of aging (Ferris, 1990). Drugs which may enhance acetylcholine synthesis or release such as phosphatidylcholine, 3,4-diaminopyridine (Ferris, 1990; Harvey and Rowan, 1990) and choline (Sitaram and coworkers, 1978a), as well as the muscarinic cholinergic agonist arecoline (Tariot and coworkers, 1988), have also been proposed for treatment of Huntington's disease.
The use of L-dopa as the primary therapeutic agent for treatment of Parkinson's disease may serve as an example of the limitations of present technology. Citing earlier work, Robin (1991) has noted that " . . . chronic exposure to high dose L-dopa may accelerate the progression of Parkinson's disease." Indeed, clinical benefits to be obtained from L-dopa therapy are predictably limited to perhaps three to five years. After that period, continued use of L-dopa will not provide clinical benefit. This situation exists because L-dopa therapy depends on conversion of this physiological precursor into dopamine within a population of substantia nigra neurons which is selectively deteriorating in this disease. Once the last of these nerve cells is gone, the therapeutic strategy has lost its physiological basis.
However, use of the invention originally disclosed in U.S. patent application Ser. No. 07/660,561, filed Feb. 21, 1991, now abandoned, may serve to sequester and remove aldehyde and ketone products of lipid peroxidation process known to exist in parkinsonian substantia nigra tissue (Fahn, 1989; Youdim, 1990). This may at least partially address the etiological basis of the disease. Use of the invention originally disclosed in U.S. patent application Ser. No. 07/660,561, filed Feb. 21, 1991, now abandoned, in combination with, or originally prior to, present L-dopa therapeutic technology should serve to further advance prior art technology for treatment of Parkinson's disease. Hence, the invention described herein may serve to delay the necessity of initiating L-dopa therapy and, once L-dopa therapy has begun, may serve to permit use of a smaller dosage of the dopamine precursor. This, in turn, may permit a decreased level of metabolic stress on substantia nigra nerve cells.
Similar reasoning applies in the case of prospective treatment of Alzheimer's disease and age-related neuron degeneration. As noted by Ceballos and coworkers (1990):
This background information, in addition to that provided in U.S. patent application Ser. No. 08/026,617, filed Feb. 23, 1993, now abandoned, provides the conceptual basis for use of the invention described herein for treatment of humans suffering from Alzheimer's disease and age-related neuron degeneration. Recently reported strategies for clinical treatment of Alzheimer's disease include possible use of (a) vasodilator or other nootropic direct brain metabolic enhancer drugs such as idebenone (Nagaoka and coworkers, 1984; Shimizu, 1991), propentophylline (Hindmarch and Subhan, 1985; Shimizu, 1991), pentoxifylline (Moos and Hershenson, 1989), citicoline (Moos and Hershenson, 1989), piracetam (Franklin and coworkers, 1986; Becker and Giacobini, 1988), oxiracetam (Spignoli and Pepeu, 1987; Villardita and coworkers, 1987), aniracetam (Cumin and coworkers, 1982; Spignoli and Pepeu, 1987), pramiracetam (Franklin and coworkers, 1986), pyroglutamic acid (Spignoli and coworkers, 1987; Porsolt and coworkers, 1988), tenilsetam (Moos and coworkers, 1988, pg. 362; Pepeu and Spignoli, 1989), rolziracetam (Moos and Hershenson, 1989), etiracetam (Franklin and coworkers, 1986), dupracetam, vinpocetine (Groo and coworkers, 1987; Moos and Hershenson, 1989), ebiratide (Hock and coworkers, 1988), beta-carbolines (Jensen and coworkers, 1987), naloxone (Jensen and coworkers, 1980; Reisberg and coworkers, 1983; Rush, 1986; Henderson and coworkers, 1989; Pepeu and Spignoli, 1990, pgs. 247-248; Cooper, 1991; Whitehouse, 1991), ergoloid mesylates such as Hydergine (Moos and Hershenson, 1989; Cooper, J. K., 1991), bromvincamine (Moos and Hershenson, 1989), cyclandelate (Ananth and coworkers, 1985; Moos and Hershenson, 1989), isoxsuprene (Moos and Hershenson, 1989), nafronyl (Moos and Hershenson, 1989), papaverine (Moos and Hershenson, 1989), suloctidil (Moos and Hershenson, 1989), vinburnine (Moos and Hershenson, 1989), vincamine (Moos and Hershenson, 1989), vindeburnol (Moos and Hershenson, 1989), flunarizine (Holmes and coworkers, 1984; Moos and Hershenson, 1989; Cooper, 1991), nimodipine (Moos and Hershenson, 1989; Cooper, 1991; Whitehouse, 1991), nicergoline (sermion) (Battaglia and coworkers, 1989; Moos and Hershenson, 1989), razobazam (Hock and McGaugh, 1985; Moos and Hershenson, 1989), exifone (Moos and Hershenson, 1989), rolipram (Moos and Hershenson, 1989), sabeluzole (Clincke and coworkers, 1988; Moos and Hershenson, 1989), phosphatidylserine (Delwaide and coworkers, 1986; Zanotti and coworkers, 1986; Amaducci and coworkers, 1987; Moos and Hershenson, 1989; Ferris, 1990; Wurtman and coworkers, 1990, pg. 123; Cooper, 1991)) and ifenprodil (Carron and coworkers, 1971); (b) neurotransmission enhancer drugs (Shimizu, 1991) such as amantadine, calcium hopantenate (Umeno and coworkers, 1981), lisuride, bifemelane (Kikumoto and coworkers, 1981; Egawa and coworkers, 1987; Tobe and coworkers, 1981) and indeloxazine (Tachikawa and coworkers, 1979; Hayes and Chang, 1983; Mizuno and coworkers, 1988); (c) tiapride, a selective D.sub.2 blocker (Peselow and Stanley, 1982; Shimizu, 1991); (d) psychotherapeutic drugs such as haloperidol, bromperidol (Niemegeers and Janssen, 1979; Woggon and coworkers, 1979), thioridazine, thiothixene, fluphenazine, perphenazine and molindone (Shimizu, 1991; and Cooper, 1991); (e) antioxidants such as tocopherols, ascorbic acid (Ceballos and coworkers, 1990) or deferoxamine (Halliwell, 1991, pg. 593), as oxidant stress appears to be part of the cytopathology of Alzheimer's disease; (f) acetylcholinesterase inhibitors such as physostigmine (optionally with lecithin) (Thal and Altman Fuld, 1983; Bartus and Dean, 1988; Becker and Giacobini, 1988; Beller and coworkers, 1988; Stern and coworkers, 1988; Thal and coworkers, 1989), heptylphysostigmine (Brufani and coworkers, 1987; Moos and Hershenson, 1989), tetrahydroaminoacridine (tacrine) (Summers and coworkers, 1986; Bartus and Dean, 1988; Mesulam and Geula, 1990, pg. 235) and a hydroxy derivative thereof, (.+-.)-9-amino-1,2,3,4-tetrahydroacridin-1-ol (Shutske and coworkers, 1988; Davies, 1991, pg. S-25), metrifonate (Becker and Giacobini, 1988), velnacrine maleate (Cooper, 1991; Cutler and coworkers, 1992), galanthamine (Nivalin) (Ferris, 1990; Sweeney and coworkers, 1990), sulfonyl fluorides such as methanesulfonyl fluoride (Moos and Hershenson, 1989) and phenylmethylsulfonyl fluoride (Ferris, 1990; Pope and Padilla, 1990), huperzines A and B (Tang and coworkers, 1989; Ferris, 1990), edrophonium (Flood and coworkers, 1988) and miotine and derivatives therof (Moos and Hershenson, 1989); (g) calcium channel blocker agents such as diltiazem, verapamil, nifedipine, nicardipine, isradipine, amlodipine and felodipine; (h) biogenic amines and agents related thereto (Moos and Hershenson, 1989) such as clonidine, a noradrenergic alpha.sub.2 -receptor agonist (Ferris, 1990; Cooper, 1991), guanfacine, an adrenergic agonist (Cooper, 1991), alaproclate, fipexide, zimeldine and citalopram; (i) anti-rage drugs such as propranolol, carbamazepine and fluoxetine (Cooper, 1991); (j) minor tranquilizers such as benzodiazepine agents (Cooper, 1991); (k) angiotensin-converting enzyme inhibitors such as captopril (Capoten, or in combination with hydrochlorothiazide, Capozide) (Ondetti, 1988; Ferris, 1990; Cooper, 1991; Whitehouse, 1991); (1) agents which may enhance acetylcholine synthesis, storage or release (Moos and Hershenson, 1989) such as phosphatidylchloine, 4-aminopyridine (Sellin and Laakso, 1987; Ferris, 1990; Harvey and Rowan, 1990, pg. 228; Wurtman and coworkers, 1990, pg. 122), bifemelane, 3,4-diaminopyridine (Bartus and Dean, 1988), choline (Summers and coworkers, 1986; Harvey and Rowan, 1990, pgs. 229-232; Sitaram and coworkers, 1978a; Siteram and coworkers, 1978b), vesamicol (Moos and Hershenson, 1989), secoverine, bifemelane, tetraphenylurea (Moos and Hershenson, 1989) and nicotinamide (Moos and Hershenson, 1989); (m) postsynaptic receptor agonists such as arecoline (Sitaram and coworkers, 1978b; Tariot and coworkers, 1988), oxotremorine (Cho and coworkers, 1964; Baratti and coworkers, 1984; Flood and coworkers, 1988; Ferris, 1990), bethanechol (Chan-Palay, 1990, pg. 255; Ferris, 1990), ethyl nipecotate (Moos and Hershenson, 1989) and levacecarnine (Bonavita, 1986; Tempesta and coworkers, 1987; Parnetti and coworkers, 1992); (n) N-methyl-D-aspartate glutamate receptor antagonists such as milacemide (Ferris, 1990; Dysken and coworkers, 1992); (o) ganglioside GM.sub.1, as a factor which may potentiate the release of nerve growth factor (Ferris, 1990); (p) mixed cow brain gangliosides (Cronassial) as a composition for induction of nerve axonal sprouting (Bradley, 1990); (q) specific monoamine oxidase-A inhibitors such as moclobemide (Larsen and coworkers, 1984; Wiesel and coworkers, 1985; Burkard and coworkers, 1989; Anand and Wesnes, 1990, pgs. 261-268; Chan-Palay, 1992); (r) monoamine oxidase B inhibitors such as selegiline (Cooper, 1991); (s) thiamine (Cooper, 1991) and a derivative thereof, sulbutiamine (Micheau and coworkers, 1985); (t) D-cycloserine (Francis and coworkers, 1991); (u) anfacine (Ferris, 1990): (v) linopirdine; (w) nonsteroidal anti-inflammatory agents such as those recognized for treatment of rheumatoid arthritis, as well as deferoxamine (McGeer and Rogers, 1992); and (x) serotoneregic receptor antagonists such as ketanserin (Ketan) and mianserin (Mian) (Normile and Altman, 1988).
Some published work has reported that L-deprenyl (selegiline) may work in part by slowing the aging process (Sanchez-Ramos, 1991, pg. 400). Monoamine oxidase B (MAO-B) activity, which is thought to increase with aging in some areas of the brain, generates H.sub.2 O.sub.2, which in turn may generate neurocytotoxic hydroxyl free radicals (HO.sup.-) and leads to subsequent lipid peroxidation. Hence, use of MAO-B inhibitors such as L-deprenyl may have an anti-aging clinical effect (Youdim, 1990). The use of L-deprenyl as a clinical agent for treatment of canine age-related dementia is an example of the potential veterinary applications of the prior art drugs included in this invention (Milgram, 1992).
Other recognized experimental anti-aging agents include (a) vasodilator and other nootropic direct brain metabolic enhancer drugs such as beta-carbolines (Moos and Hershenson, 1989), sabeluzole (Clincke and coworkers, 1988; Moos and Hershenson, 1989; Crook, 1990), razobazam (Hock and McGaugh, 1985; Moos and Hershenson, 1989), exifone (Moos and Hershenson, 1989), idebenone (Moos and Hershenson, 1989), pentoxifylline (Moos and Hershenson, 1989), rolipram (Moos and Hershenson, 1989), vinpocetine (Moos and Hershenson, 1989), citicoline (Moos and Hershenson, 1989), bromvincamine (Moos and Hershenson, 1989), cyclandelate (Ananth and coworkers, 1985; Moos and Hershenson, 1989), ergoloid mesylates such as Hydergine (Moos and Hershenson, 1989), isoxsuprene (Moos and Hershenson, 1989), nafronyl (Moos and Hershenson, 1989), nicergoline (Moos and Hershenson, 1989), papaverine (Moos and Hershenson, 1989), suloctidil (Moos and Hershenson, 1989), vinburnine (Moos and Hershenson, 1989), vincamine (Moos and Hershenson, 1989), vindeburnol (Moos and Hershenson, 1989), nimodipine (Moos and Hershenson, 1989), naloxone (Jensen and coworkers, 1980; Rush, 1986), piracetam (Moos and Hershenson, 1989), pramiracetam (Moos and Hershenson, 1989), aniracetam (Cumin and coworkers, 1982; Moos and Hershenson, 1989), oxiracetam (Franklin and coworkers, 1986; Spignoli and Pepeu, 1987; Crook, 1990), rolziracetam (Moos and Hershenson, 1989), tenilsetam (Pepeu and Spignoli, 1989; Saletu and coworkers, 1989), flunarizine, phosphatidylserine (Delwaide and coworkers, 1986; Zanotti and coworkers, 1986; Amaducci and coworkers, 1987; Crook and Larrabee, 1991), dupracetam (Ferris, 1990; Pepeu and Spignoli, 1990; Cooper, 1991; Whitehouse, 1991), propentophylline (Hindmarch and Subhan, 1985), ebiratide, pyroglutamic acid and etiracetam; (b) acetylcholinesterase inhibitors such as miotine and derivatives thereof (Moos and Hershenson, 1989), physostigmine (Davis and coworkers, 1978; Bartus and Dean, 1988; Beller and coworkers, 1988; Stern and coworkers, 1988), heptylphysostigmine (Brufani and coworkers, 1987; Moos and Hershenson, 1989), tacrine (Bartus and Dean, 1988; Moos and Hershenson, 1989) and a hydroxy derivative thereof, (.+-.)-9-amino-1,2,3,4-tetrahydroacridin-1-ol (Shutske and coworkers, 1988), sulfonyl fluorides such as methanesulfonyl fluoride (Moos and Hershenson, 1989; Pope and Padilla, 1990), huperzine A (Moos and Hershenson, 1989), huperzine B (Tang and coworkers, 1989), edrophonium (Flood and coworkers, 1988), galanthamine (Nivalin) (Sweeney and coworkers, 1990), metrifonate (Moos and Hershenson, 1989) and velnacrine (Cutler and coworkers, 1992); (c) cholinergic muscarinic agonists such as arecoline (Sitaram and coworkers, 1978b; Tariot and coworkers, 1988), oxotremorine (Cho and coworkers, 1964; Baratti and coworkers, 1984; Flood and coworkers, 1988), bethanechol (Moos and Hershenson, 1989), ethyl nipecotate (Moos and Hershenson, 1989) and levacecarnine (Bonavita, 1986; Tempesta and coworkers, 1987; Moos and Hershenson, 1989; Maccari and coworkers, 1990; Parnetti and coworkers, 1992); (d) biogenic amines and co-agents related thereto such as clonidine (Moos and Hershenson, 1989), alaproclate (Moos and Hershenson, 1989; Ferris, 1990), guanfacine (Moos and Hershenson, 1989; Crook, 1990, pg. 213), fipexide (Moos and Hershenson, 1989), zimeldine (Moos and Hershenson, 1989) and citalopram (Moos and Hershenson, 1989); (e) anfacine (Ferris, 1990); (f) acetylcholine synthesis, storage or release modulators such as choline (Sitaram and coworkers, 1978a; Sitaram and coworkers, 1978b; Franklin and coworkers, 1986), phosphatidylcholine (Crook, 1990, pg. 212), 4-aminopyridine (Sellin and Laakso, 1987; Wurtman and coworkers, 1990), 3,4-diaminopyridine (Bartus and Dean, 1988; Harvey and Rowan, 1990, pgs. 229-232), vesamicol (Moos and Hershenson, 1989), tetraphenylurea (Moos and Hershenson, 1989), secoverine (Moos and Hershenson, 1989), bifemelane (Moos and Hershenson, 1989) and nicotinamide (Moos and Hershenson, 1989); (g) N-methyl-D-aspartate glutamate receptor antagonists (Clineschmidt and coworkers, 1982; Crook, 1990, pg. 214; Ferris, 1990) such as milacemide (Moos and Hershenson, 1989), dizocilpine (Moos and Hershenson, 1989) and memantine (Moos and Hershenson, 1989); (h) ganglioside GM.sub.1 (Moos and Hershenson, 1989); (t) angiotensin-converting enzyme inhibitors such as captopril (Ondetti, 1988; Moos and Hershenson, 1989; Crook, 1990; Ferris, 1990) and quinapril (Moos and Hershenson, 1989); (j) prostaglandin B.sub.1 oligomers (PGB.sub.x, Franson and coworkers, 1991) and other antioxidants (Ceballos and coworkers, 1990); (k) the free radical scavenger agent acetylhomocysteine thiolactone (Citiolase) (Totaro and coworkers, 1985); (l) sulbutiamine, a derivative of thiamine (Micheau and coworkers, 1985); and (m) serotoneregic receptor antagonists such as ketanserin (Ketan) and mianserin (Mian) (Normile and Altman, 1988).
Drugs recognized or suggested as experimental symptomatic agents for treatment of tinnitus (nerve deafness) include: (a) antidepressants or antianxiety medications such as amitriptyline HCl (Elavil), perphenazine/amitriptyline combinations (such as Triavil), alprazolam (Xanax) and triptolene: (b) anticonvulsants such as primidone (Mysoline), phenytoin (Dilantin) and carbamazepine (Tegretol); (c) intraveneous lidocaine (Schleuning, 1991); (d) tocainide and flecinide, derivatives of lidocaine which can be administered orally; (e) flunarizine; (f) nicotinamide; (g) aminooxyacetic acid; (h) praxilene; (i) aniracetam; and (j) piracetam (Brummett, 1989). In addition in vitro evidence has been presented which indicates that retinoic acid has a stimulatory effect on differentiation of cochlear hair cells (Sporn and coworkers, 1977; Ott and Lachance, 1979; Travis, 1992).
Presently recognized clinical therapeutic technology for treatment of diabetes, or experimental treatment of diabetes includes use of: (a) various insulin derivatives and compositions such as Humulin 70/30, Mixtard 70/30 or Novolin 70/30; (b) various oral sulfanilamide derivative hypoglycemic agents such as tolbutamide (Orinase), acetohexamide, tolazamide (Tolinase), chlorpropamide (Diabenese), glipizide (Glucotrol) and glyburide (Diabeta, Micronase) (Reed and Mooradian, 1991); (c) vitamin supplements such as vitamin C, vitamin B.sub.1 and vitamin B.sub.6 ; (d) angiotensin-converting enzyme inhibitors such as captopril, epi-captopril and zofenopril, which also have free radical scavenging properties (Westlin and Mullane, 1988); (e) anti-hyperlipidemia agents such as fibric acid derivatives, including gemfibrozil (Lopid) (Garg and Grundy, 1990), bezafibrate (Olsson and Lang, 1978a; Olsson and Lang, 1978b; Zimmermann and coworkers, 1978; Monk and Todd, 1987) and fenofibrate (Elsom and coworkers, 1976; Wulfert and coworkers, 1976); metformin (Hermann, 1979); guar gum (Lalor and coworkers, 1990); 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors such as lovastatin (Mevacor) (Garg and Grundy, 1990), pravastatin and simvastatin; acipimox, an analogue of nicotinic acid (Fuccella and coworkers, 1980; Lovisolo and coworkers, 1981); nicotinic acid (Fuccella and coworkers, 1980); or bile acid sequestrants such as cholestyramine (Garg and Grundy, 1990) and colestipol (Durrington, 1991; Stern and Haffner, 1991); (f) antioxidants such as probucol (Halliwell, 1991, pg. 583; Stern and Haffner, 1991) or PGB.sub.x, a polymerized derivative of prostaglandin B.sub.1 (Moss and coworkers, 1978; Polis and Polis, 1979; Polis and Cope, 1980; Franson and coworkers, 1991) and, by inference, 2-aminomethyl-4-tert-butyl-6-iodophenol,2-aminomethyl-4-tert-butyl-6-propi onylphenol and 2,6-di-tert-butyl-4-[2'-thenoyl]phenol (Swingle and coworkers, 1985; Halliwell, 1991, pg. 596); (g) immunosuppressive drugs such as cyclosporine (Sandimmune) or azathioprine/glucocorticoids (Marks and Skyler, 1991; Skyler, 1991); (h) agents which decrease blood platelet aggregation such as salicylates and dipyridamole (Persantine) (Skyler, 1991); (i) agents which decrease blood viscosity such as pentoxifylline (Trental) (Skyler, 1991); (j) purified cow brain mixed gangliosides (Cronassial) (Bradley, 1990); (k) various agents for treatment of diabetes-related nephrotic syndrome such as furosemide, metolazone, lovastatin, heparin, warfarin, and aminoguanidine (Brownlee and coworkers, 1986); (l) aldose reductase inhibitors (Skyler, 1991) such as sorbinil (Sima and coworkers, 1988), alrestatin (Kikkawa and coworkers, 1983); (E)-3-carboxymethyl-5-[(2E)-methyl-3-phenylpropenylidene]rhodanine (Kikkawa and coworkers, 1983), statil (Daniels and Hostetter, 1989), and tolrestat (Dyck, 1989); and (m) analgesic agents such as acetaminophen for treatment of chronic pain (Weglicki and coworkers, 1990; Cooper, 1991; Guthrie, 1991; Skyler, 1991; Woodley and Whelan, 1992, pg. 224).
Various immunosuppressive agents have been proposed for the treatment of multiple sclerosis (Goodin, 1991). These include: (a) azathioprine (Ellison and coworkers, 1988); (b) copolymer-1 (Bornstein and coworkers, 1988); (c) cyclosporine (Dommasch, 1988); (d) interferons (Knobler, 1988); (e) corticosteroids (Carter and coworkers, 1988); and (f) cyclophosphamide (Carter and coworkers, 1988). Other experimental therapeutic agents for treatment of multiple sclerosis include the use of 4-aminopyridine (Sellin and Laakso, 1987) and 3,4-diaminopyridine (Bever and coworkers, 1990).
Recent studies on amyotrophic lateral sclerosis have included experimental use of purified cow brain mixed gangliosides, and this agent has also been used in experimental clinical trials on alcoholic polyneuropathy and hereditary motor and sensory neuropathies (HMSN) (Bradley, 1990). Thyrotropin releasing factor (Bradley, 1990), serine, glycine and L-threonine (Roufs, 1991) have also been proposed as a possible therapeutic agents for treatment of amyotrophic lateral sclerosis. Other agents which have been proposed as therapeutic agents for treatment of alcoholism include (a) tiapride, a substituted benzamide (Shaw and coworkers, 1987); (b) 4-aminopyridine (Sellin and Laakso, 1987); (c) physostigmine (Stojek and coworkers, 1986); (d) piracetam (Moos and coworkers, 1988, pg. 361); and (e) cyclandelate (Ananth and coworkers, 1985). 3,4-Diaminopyridine is another agent which has been proposed for the treatment of hereditary motor and sensory neuropathy (Windebank, A. J., Mayo Clinic, study in progress as of 1993).
Numerous prior art publications have disclosed that vitamin E (alpha-tocopherol) functions physiologically as a lipid-soluble antioxidant free radical trapping agent. Prior art publications have also described methionine as a water-soluble agent, an essential amino acid, an antioxidant and a free radical trapping agent. Many attempts have been made to clinically treat neuromuscular diseases with antioxidants, generally with little success. For example, Williams and coworkers (1990) reported that dietary supplementation with vitamin E had no significant effect on the clinical status of HMSN patients, while Gerster (1991) reported that dietary supplementation with a combination of vitamin C, vitamin E, beta-carotene, and selenium had the effect of halting or improving degenerative retinal changes in some patients having either age-related macular degeneration or diabetic retinopathy. Additional work of this conceptual nature includes the work of Muller (1990), who reported that alpha-tocopherol has a positive effect on the clinical status of patients suffering from tardive dyskinesia. Yet none of these studies has disclosed the invention contained in copending U.S. patent application Ser. No. 08/026,617, filed Feb. 23, 1993, now abandoned that is, treatment of neurodegenerative diseases by use of primary agents which are primary amine and amine-related substances to inhibit aldehyde-mediated protein and lipid crosslinking, said primary agents capable of being used in combination with known antioxidants and related substances as co-agents.
Vitamin C (ascorbic acid) is widely recognized as a water-soluble antioxidant vitamin. However, numerous published studies which have appeared since 1980 document that vitamin C also can act physiologically as a pro-oxidant (Gutteridge and Wilkins, 1982), an agent which stimulates lipid peroxidation (Chojkier and coworkers, 1989, pgs. 16957 and 16961), and that it is a strong protein glycosylating agent (Ortwerth and Olesen, 1988, pgs. 12, 14, 16, 18 and 20). Thus, for example, in vitro studies have documented the ability of vitamin C to accelerate the process of cataract formation (Slight and coworkers, 1990, pgs. 369-373). In addition, some evidence suggests that ascorbic acid may act as a factor which stimulates certain reactions which are characteristic of inflammatory diseases. For example, the presence of ascorbic acid in the synovial fluid of the arthritic joint may contribute to degradation of hyaluronic acid (Wong and coworkers, 1981; Higson and coworkers, 1988). In light of such information, use of ascorbic acid has been withdrawn from the invention originally disclosed in U.S. patent application Ser. No. 07/660,561, filed Feb. 21, 1991, now abandoned.
As discussed in U.S. patent application Ser. No. 08/026,617, filed Feb. 23, 1993, now abandoned a considerable body of prior art publications has provided evidence suggesting that the etiologies of certain neurodegenerative diseases include evidence of chemical crosslinking of neurofilaments. Such studies include work on hereditary motor and sensory neuropathies (Hughes and Brownell, 1972; Brimijoin and coworkers, 1973; van Weerden and coworkers, 1982; and Goebel and coworkers, 1986), giant axon neuropathy (Prineas and coworkers, 1976), diabetic polyneuropathy (Yamamura and coworkers, 1982; Sidenius and Jakobsen, 1982; and Tomlinson and Mayer, 1984), Alzheimer's disease (Wisniewski and coworkers, 1970; Iqbal and coworkers, 1978, and Wisniewski and coworkers, 1982, pp. 110-112), Down's syndrome (Goodison and coworkers, 1989), Pick's disease (Yoshimura, 1989), Parkinson's disease (Oppenheimer, 1976, pp. 612-614; and Cohan, 1989, pg. 167), amyotrophic lateral sclerosis (Carpenter, 1968), infantile spinal muscular atrophy (Lee and coworkers, 1989), Friedreich's ataxia (Lamarche and coworkers, 1982) and alcoholic polyneuropathy (Appenzeller and Richardson, 1966).
Likewise, evidence of increased deposition of lipofuscin in various neurodegenerative diseases has been presented. This observation has been documented in studies on amyotrophic lateral sclerosis (Carpenter, 1968), Guam Parkinsonism-dementia (Tan and coworkers, 1981), Alzheimer's disease (and Tsuchida and coworkers, 1987; Moran and Gomez-Ramos, 1989;), Huntington's disease (Tellez-Nagel and coworkers, 1974), Meniere's disease (Ylikoski and coworkers, 1980), and juvenile ceroid-lipofuscinosis (Schwendemann, 1982). Heart lipofuscin has been shown to have the following general composition: lipids, 20-50%; protein, 30-60%; and strongly pigmented resin-like hydrolysis-resistant material, 9-20%. Although the exact nature of the hydrolysis-resistant chemical bonds remains to be unequivically defined, the similarity between lipofuscin fluorescence and that of Schiff bases formed between malonaldehyde and primary amines suggests that similar chemical crosslinks may be part of lipofuscin structure (Tsuchida and coworkers, 1987).
The results of several published research studies suggest that dysfunctional lipid peroxidation may be a contributing factor in the etiology of Parkinson's disease (Fahn, 1989), multiple sclerosis (Hunter and coworkers, 1985) and Duchenne muscular dystrophy (Kar and Pearson, 1979; Jackson and coworkers, 1984; Hunter and Mohamed, 1986).
Age-related changes share much in common with other disease entities discussed in this invention. At the biochemical level, the two most clearly defined pathological events within aging mammalian cells appear to be (1) the progressive accumulation of lipofuscin and (2) concomitant appearance of high molecular weight protein aggregates and/or polymeric lipid-protein complexes (Shimasaki and coworkers, 1984). Age-onset peripheral nerve damage has been recognized in both man and experimental animals. Such polyneuropathy is extremely common in the elderly (Cohan, 1989). Examination of human sural nerve biopsies has revealed age-related degeneration of both myelinated and non-myelinated fibers. This process includes the occurrence of unusual inclusions within axons consisting of filament bundles which appear more dense than those of normal neurofilaments (Ochoa and Mair, 1969). As peripheral, autonomic and central nervous system neurons lose functional ability as part or the aging process a variety of body functions under their control are adversely affected.
Autonomic nervous system functions include urinary continence, peristaltic movement of the digestive tract, sexual response and breathing. Forms of neurological dysfunction lying within the scope of this invention which may cause urinary incontinence include: Alzheimer's senile dementia, demyelinating diseases such as multiple sclerosis, peripheral nerve lesions, diabetes mellitus and alcoholic polyneuropathy (Palmer, 1985, pg. 27). Causes of urinary incontinence which may be classified as urological/gynecological, psychological or environmental (Palmer, 1985, pg.22) do not fall within the scope of this invention. Drugs which are presently recognized for use in treatment include cholinergics such as bethanechol, anti-cholinergics such as belladonna and alpha-adrenergics such as ephedrine (Palmer, 1985, pg. 58). None of these therapeutic agents have been heretofore recognized as drugs falling within the pharmacological scope of U.S. patent application Ser. No. 08/026,617, filed Feb. 23, 1993, now abandoned, although this inventor regards the alpha-adrenergics ephedrine, which contains a secondary amine group, and phenylpropanolamine, which contains a primary amine group, as potential carbonyl-trapping agents.
Peristaltic movement of the digestive tract, which is controlled by the autonomic nervous system, may be adversely affected due to aging, diabetes (Bergmann and coworkers, 1992) or other clinical disorders. Drugs presently recognized for the treatment of gastroesophageal reflux disease, hypoperistalsis and/or delayed gastric emptying include (a) metoclopramide (Reglan); (b) cisapride (Prepulsid) (Bergmann and coworkers, 1992); (c) famotidine (Pepcid); (d) cimetidine (Tagamet); (e) ranitidine (Zantac); (f) omeprazole (Prilosec); and galanthamine (Sweeney and coworkers, 1990).
In their study on human senile and diabetic cataracts, Rao and Cotlier (1986) noted evidence that crosslinking of lens proteins via nonenzymatic glycosylation appears to be an underlying pathological mechanism for both cataract types. In their analysis of senile cataracts these investigators observed statistically significant decreases in soluble protein content, increases in insoluble proteins, decreases in free epsilon-amino groups of insoluble proteins and increases in observed 5-hydroxymethyl furfural levels (that is, reducible Maillard products) in insoluble proteins. Similar data were obtained from diabetic cataracts. Earlier studies showed the appearance of covalently crosslinked protein polymers during senile cataract formation (Selkoe and coworkers, 1982). Evidence of increased lipid peroxidation in the aged human lens has also been presented (Bhuyan and coworkers, 1986).
In addition, several published studies have presented evidence which implicates lipid peroxidation products in the etiology of atherosclerosis (Halliwell, 1991, pg. 583). 4-Hydroxy-2,3-transnonenal covalently binds to lysine and other peptide residues of low-density lipoprotein much more readily than malondialdehyde. Hence, it (as well as other aldehydes) may play a role in the etiology of atherosclerotic lesions (Jurgens and coworkers, 1986; and Esterbauer and coworkers, 1987). As summarized by Steinbrecher (1987), there is reason to believe that reactive lipid peroxidation agents form Schiff base adducts with the lysine epsilon-amino groups of low density lipoproteins (LDL). Such modified LDL's are recognized by high-affinity acetyl-LDL receptors located on macrophages, which results in lipid accumulation. Lipid-laden macrophages appear to be precursors of the foam cells which populate early atherosclerotic lesions (Steinbrecher, 1987). Use of the invention of U.S. patent application Ser. No. 08/026,617, filed Feb. 23, 1993, now abandoned, in combination with previously recognized medicaments for treatment of atherosclerosis, hypertension and ischemic heart disease, as defined herein, may provide additional clinical benefit for patients suffering from these chronic, age-related diseases. Previously recognized drugs for treatment of atherosclerosis include hypolipidemic agents such as fenofibrate (Elsom and coworkers, 1976; Wulfert and coworkers, 1976), bezafibrate (Olsson and Lang, 1978a; Olsson and Lang, 1978b; Zimmermann and coworkers, 1978; Monk and Todd, 1987), metformin (Hermann, 1979), nicotinic acid (Fuccella and coworkers, 1980), acipimox (Fuccella and coworkers, 1980; Lovisolo and coworkers, 1981) and guar gum (Lalor and coworkers, 1990), as well as antioxidants such as probucol (Halliwell, 1991, pg. 583; Stern and Haffner, 1991) and prostaglandin B.sub.1 oligomers (PGB.sub.x) (Moss and coworkers, 1978; Polis and Cope, 1980). Previously known medicaments for treatment of hypertension (Woodley and Whelan, 1992, pp. 64-75) include diuretics, beta-adrenergic antagonists, calcium antagonists, angiotensin-converting enzyme inhibitors, centrally acting alpha-adrenergic agonists, direct-acting vasodilators, alpla-adrenergic antagonists and peripherally acting anti-adrenergic agents. At least one peptide-based renin inhibitor (A-725517, Abbott Laboratories) has also been mentioned as a prospective anti-hypertensive agent (Kleinert and coworkers, 1992). Previously known medicaments for treatment of ischemic heart disease include nitroglycerin, beta-adrenergic antagonists, calcium channel antagonists and aspirin (Woodley and Whelan, 1992, pp. 81-84). Recognized ventricular antiarrhythmic drugs include sotalol, mexilitene, propafenone, quinidine gluconate, procainamide and pirmenol (Toivonen and coworkers, 1986). Some published information indicates that at least part of the physiological activity of some cardioprotective drugs may be due to their possessing certain free radical scavenging and/or antioxidant properties. This appears to be the case for (a) beta-blocker agents such as propranolol, pindolol, metoprolol, atenolol and sotalol; (b) calcium channel blockers such as nifedipine, verapamil and diltiazem; (c) probucol; and (d) angiotensin converting enzyme inhibitors such as captopril, epicaptopril and zofenopril (van Gilst and coworkers, 1986; Ondetti, 1988; Weglicki and coworkers, 1990).
This inventor has published the findings of a study which may describe part of the physiological basis of one of the hereditary motor and sensory neuropathies (Shapiro and coworkers, 1986; Shapiro and Kahn, 1990). In this study urine samples from five autosomal dominant chromosome 17 HMSN patients of the same family and five urine samples from age- and sex-matched normal control subjects were examined. By use of gas chromatography/mass spectrometry the urine concentrations of approximately 150 organic acids could be estimated in each sample. Average HMSN organic acid values differed most notably from normal values in a set of three physiologically related metabolites, 5-hydroxymethyl-2-furoic acid, 2,5-furandicarboxylic acid and 5-carboxy-2-furoylglycine. Average patient urine concentrations of these three organic acids were 29% 50% and 37% of controls, respectively.
5-Carboxy-2-furoylglycine is a mono-glycine conjugate of 2,5-furandicarboxylic acid. Hence 2,5-furandicarboxylic acid was measured directly as the dicarboxylic acid and indirectly as its mono-glycine conjugate. Glycine conjugation is a well recognized liver detoxication/excretion reaction, applied broadly to the ##STR1## carboxylic acid products of many endogenous metabolites, dietary components and drugs (Williams, 1959, pp. 349-353).
Previous research studies have determined that 5-hydroxymethyl-2-furoic acid and 2,5-furandicarboxylic acid are oxidation products of an aldehyde precursor, 5-hydroxymethyl-2-furfural (Jellum and coworkers, 1973). Decreased levels of furancarboxylic acid excretion suggest that this metabolite, and possibly other aldehyde precursors suck as 2,5-furandialdehyde, is not being detoxicated and cleared in a normal manner. Several enzymes may be involved in the normal detoxication of furanaldehydes. Oxidation of furanaldehydes to carboxylic acid products is known to occur in mammalian tissues (Williams, 1959, pp. 550-551), but a specific furanaldehyde dehydrogenase has not been characterized.
Prior art studies have demonstrated the existance of several mammalian aldehyde dehydrogenases which possess wide substrate specificities (Hjelle and Petersen, 1983; Lindahl and Evces, 1984). These are NAD(P)-dependent enzymes. Normal detoxication of furanaldehydes may involve roles for one or more of these enzymes, or their flavin-dependent counterpart, and the HMSN patients studied by this inventor and coworkers may have a genetic defect in this process.
5-Hydroxymethyl-2-furfural should be regarded as a potential protein crosslinking agent (Jellum and coworkers, 1973, pg. 200). 2,5-Furandialdehyde is even more suspect as a potential crosslinking agent, as it bears two highly reactive aldehyde groups. It is a close structural analogue of 2,5-hexanedione, a potent chemical peripheral neurotoxin implicated in the covalent crosslinking of neurofilaments. ##STR2##
Hence 2,5-furandialdehyde appears to be a particularly interesting metabolite. It is cleared from the body only with difficulty in patients having a genetic peripheral neuropathy; and its size, three dimensional shape and analogous bi-carbonyl structure make it structurally related to a chemical known to induce peripheral neuropathy in mammals after relatively trace levels of exposure (Krasavage and coworkers, 1980). Covalent chemical crosslinking of neurofilaments has been shown to be the basis of 2,5-hexanedione neurotoxicity (Carden and coworkers, 1986).
There is reason to believe that 5-hydroxymethyl-2-furfural and 2,5-furandialdehyde can originate as by-products of either of two general areas of metabolism, that of sugars and lipids. The thought that secondary products of lipid peroxidation might include metabolites such as 5-hydroxymethyl-furanaldehyde and 2,5-furandialdehyde has attracted little, if any, attention within the biomedical research community prior to submission of U.S. patent application Ser. No. 07/660,561, filed Feb. 21, 1991, now abandoned. As described in that disclosure, 2,5-dimethyl furan appears to be a key intermediate in the process leading to the appearance of these aldehydes.
5-Hydroxymethyl-2-furfural and 2,5-furandialdehyde can also form spontaneously from glucose or fructose under mildly acidic aqueous conditions and, as they are readily generated during food cooking, they are part of the human diet. There is reason to believe that these aldehydes, among others, may play a significant role in the etiology of diabetic polyneuropathy. As discussed in U.S. patent application Ser. No. 08/026,617, filed Feb. 23, 1993, now abandoned, it is the understanding of this inventor that conversion of fructose to 5-hydroxymethyl furfural and possibly 2,5-furandialdehyde may in fact be the basis of neurotoxic consequences resulting from activation of the polyol pathway seen in diabetic polyneuropathy.
Studies during the past decade have clearly established that long-term hyperglycemia associated with diabetes leads to generalized non-enzymatic addition of reducing sugar residues to proteins via covalent addition to amine functional groups located on amino acid sidechains. Following initial addition, several structural rearrangements occur which can result in intra- and intermolecular crosslinking of proteins (Brownlee, 1990). This is a complex series of non-enzymatic reactions which are not completely defined at this time. Yet, as discussed in U.S. patent application Ser. No. 08/026,617, filed Feb. 23, 1993, now abandoned, there is reason to believe that this phenomenon is involved in diabetic vascular changes, diabetic nephropathy, cataracts, diabetic retinopathy and other secondary diabetic symptomology. Such reactions may also underlie much of the biochemistry of aging (Pongor and coworkers, 1984).
The nature of the chemical bonds responsible for holding together the neurofibrillary tangles of Alzheimer's disease (AD) and other neurodegenerative diseases is still poorly understood. What limited information is publicly available on this question is comparable with the overall inventive concept of U.S. patent application Ser. No. 08/026,617, filed Feb. 23, 1993, now abandoned; that cytotoxic consequences result from various forms of spurious covalent bond protein crosslinking, at least some forms of which may be clinically treated by the pharmacological procedures described therein.
Both AD senile plaques and neurofibrillary tangles consist largely of networks of intermediate size protein filaments helically wound in pairs having a periodicity of 80 nm (Selkoe and coworkers, 1982). Isolated paired helical filament (PHF) has proven to have remarkable properties of chemical stability. PHF chemical cross-linking bonds are not broken by sodium dodecyl sulfate, beta-mercaptoethanol, 9.5M urea, two percent Triton X-100, one percent NP-40, 6M guanidine hydrochloride, 0.2N HCl or 0.2N NaOH. As heating of PHF in the presence of either reducing agents such as beta-mercaptoethanol or detergents such as Triton X-100 or NP-40 did not solubilize PHF, bonds other than disulfide are implicated in amino acid crosslinking of this type of rigid intracellular polymer. This unusual chemical stability has seriously impeded PHF analysis by gel electrophoresis (Selkoe and coworkers, 1982). As a postulated mechanism for such unusual crosslinking Selkoe and coworkers (1982) noted that "different protein polymers in senile cataracts, terminally differentiated epidermal cells, and red blood cells are covalently crosslinked by gamma-glutamyl-epsilon-lysine sidechain bridges." Like PHF, these other protein complexes are insoluble in sodium dodecyl sulfate and not solubilized by reducing agents. Selkoe and coworkers (1982) speculated that such gamma-glutamyl-epsilon-lysine crosslinks may also form pathologically in nerve cells, as human brain contains a transglutaminase capable of acting on normal neurofilament to form an insoluble high molecular weight filamentous polymer.
The clinical neurology literature includes many descriptions of patients having an incipient form of a disease, patients showing the recognized symptoms of a disease and additional symptomology, and patients demonstrating concurrent clinical symptomology of two or more recognized disease entities. Such clinical disorders are frequently excluded from biochemical studies due to inherent problems of classification and their happenstance occurrence. Hence comparatively little research information is available on such clinical phenomena. Yet it is the understanding of this inventor that information available on the etiologies of well recognized neurological disorders, as summarized herein, can also be extrapolated to infer that the drug therapies described in this invention may also be applied with success to the incipient and more complex forms of the diseases mentioned above.